Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

• Published in: Biochemical journal 2006-06, Vol.396 (2), p.277-285
• Main Authors: Panethymitaki, Chrysoula, Bowyer, Paul W, Price, Helen P, Leatherbarrow, Robin J, Brown, Katherine A, Smith, Deborah F
• Format: Article
• Language: English
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - metabolism; Animals; Antifungal Agents - metabolism; Antifungal Agents - pharmacology; Candida albicans; Cryptococcus neoformans; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - metabolism; Kinetics; Leishmania major; Leishmania major - enzymology; Leishmania major - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Saccharomyces cerevisiae; Time Factors; Trypanosoma brucei; Trypanosoma brucei brucei - enzymology; Trypanosoma brucei brucei - metabolism
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20051886

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of